Human Molecular Genetics

by Strachan, Tom; Read, Andrew P.

• ISBN13: 9780815341840
• ISBN10: 0815341849
• Edition: 3rd
• Format: Paperback
• Copyright: 2004-06-01
• Publisher: Taylor & Francis

Summary

With this fully updated third edition, Human Molecular Genetics enters the post-genome era. The content and organization have been thoroughly revised to take account of the new knowledge and new emphases in human molecular genetics now that we have the human genome sequence.

Author Biography

Andrew Read is Professor of Human Genetics at Manchester University.

Table of Contents

Abbreviations	p. xxiii
Preface	p. xxvii
Supplementary learning aids	p. xxviii
Before we start - Intelligent use of the Internet	p. xxix
The Basics	p. 1
DNA structure and gene expression	p. 3
Building blocks and chemical bonds in DNA, RNA and polypeptides	p. 4
DNA structure and replication	p. 8
Examples of the importance of hydrogen bonding in nucleic acids and proteins	p. 10
Major classes of proteins used in the DNA replication machinery	p. 12
RNA transcription and gene expression	p. 13
RNA processing	p. 19
Translation, post-translational processing and protein structure	p. 23
Chromosome structure and function	p. 33
Ploidy and the cell cycle	p. 34
Structure and function of chromosomes	p. 34
The mitotic spindle and its components	p. 37
Mitosis and meiosis are the two types of cell division	p. 40
Studying human chromosomes	p. 44
Chromosome banding	p. 48
Human chromosome nomenclature	p. 49
Chromosome abnormalities	p. 51
Nomenclature of chromosome abnormalities	p. 53
Cells and development	p. 59
The structure and diversity of cells	p. 60
Intracellular organization of animal cells	p. 62
The cytoskeleton: the key to cell movement and cell shape and a major framework for intracellular transport	p. 64
Cell interactions	p. 66
An overview of development	p. 71
The specialization of cells during development	p. 72
Animal models of development	p. 73
Twinning in human embryos	p. 74
Where our tissues come from - the developmental hierarchy in mammals	p. 75
The diversity of human cells	p. 76
Pattern formation in development	p. 79
Morphogenesis	p. 81
Polarizing the mammalian embryo - signals and gene products	p. 82
Early human development: fertilization to gastrulation	p. 86
Extra-embryonic membranes and the placenta	p. 89
Sex determination: genes and the environment in development	p. 93
Neural development	p. 94
Conservation of developmental pathways	p. 97
Genes in pedigrees and populations	p. 101
Monogenic versus multifactorial inheritance	p. 102
Mendelian pedigree patterns	p. 102
Characteristics of the Mendelian patterns of inheritance	p. 104
The complementation test to discover whether two recessive characters are determined by allelic genes	p. 106
Complications to the basic Mendelian pedigree patterns	p. 106
Genetics of multifactorial characters: the polygenic-threshold theory	p. 111
Two common misconceptions about regression to the mean	p. 114
Partitioning of variance	p. 115
Factors affecting gene frequencies	p. 117
Hardy-Weinberg equilibrium genotype frequencies for allele frequencies p(A1) and q (A2)	p. 117
The Hardy-Weinberg distribution can be used (with caution) to calculate carrier frequencies and simple risks for counseling	p. 118
Mutation-selection equilibrium	p. 118
Selection in favor of heterozygotes for CF	p. 119
Amplifying DNA: PCR and cell-based DNA cloning	p. 121
The importance of DNA cloning	p. 122
PCR: basic features and applications	p. 123
A glossary of PCR methods	p. 124
Principles of cell-based DNA cloning	p. 129
Restriction endonucleases and modification-restriction systems	p. 129
Nonsense suppressor mutations	p. 138
The importance of sequence tagged sites (STSs)	p. 138
Cloning systems for amplifying different sized fragments	p. 138
Cloning systems for producing single-stranded and mutagenized DNA	p. 144
Cloning systems designed to express genes	p. 147
Transferring genes into cultured animal cells	p. 152
Nucleic acid hybridization: principles and applications	p. 155
Preparation of nucleic acid probes	p. 156
Principles of autoradiography	p. 159
Principles of nucleic acid hybridization	p. 161
Fluorescence labeling and detection systems	p. 164
A glossary of nucleic acid hybridization	p. 166
Nucleic acid hybridization assays using cloned DNA probes to screen uncloned nucleic acid populations	p. 168
Standard and reverse nucleic acid hybridization assays	p. 169
Hybridization assays using cloned target DNA and microarrays	p. 174
Analyzing DNA and gene structure, variation and expression	p. 181
Sequencing and genotyping DNA	p. 182
Producing single-stranded DNA sequencing templates	p. 182
Identifying genes in cloned DNA and establishing their structure	p. 186
Common classes of DNA polymorphism which are amenable to simple genotyping methods	p. 187
Studying gene expression	p. 190
Database homology searching	p. 192
Obtaining antibodies	p. 200
The human genome and its relationship to other genomes	p. 205
Genome projects and model organisms	p. 207
The ground-breaking importance of genome projects	p. 208
A genomics glossary	p. 209
Background and organization of the Human Genome Project	p. 210
How the human genome was mapped and sequenced	p. 212
Human gene and DNA segment nomenclature	p. 212
Major milestones in mapping and sequencing the human genome	p. 213
Hybrid cell mapping	p. 215
Physical mapping by building clone contigs	p. 218
Co-operation, competition and controversy in the genome projects	p. 220
Genome projects for model organisms	p. 226
Model unicellular organisms	p. 227
Model multicellular animals for understanding development, disease and gene function	p. 230
Organization of the human genome	p. 239
General organization of the human genome	p. 240
Genome copy number variation in human cells	p. 242
The limited autonomy of the mitochondrial genome	p. 243
DNA methylation and CpG islands	p. 246
Organization, distribution and function of human RNA genes	p. 247
Anticodon specificity of eukaryotic cytoplasmic tRNAs	p. 249
Organization, distribution and function of human polypeptide-encoding genes	p. 253
Human genome and human gene statistics	p. 255
Tandemly repeated noncoding DNA	p. 265
Interspersed repetitive noncoding DNA	p. 268
Human gene expression	p. 275
An overview of gene expression in human cells	p. 276
Spatial and temporal restriction of gene expression in mammalian cells	p. 276
Control of gene expression by binding of trans-acting protein factors to cis-acting regulatory sequences in DNA and RNA	p. 277
Classes of cis-acting sequence elements involved in regulating transcription of polypeptide-encoding genes	p. 283
Alternative transcription and processing of individual genes	p. 291
Alternative splicing can alter the functional properties of a protein	p. 293
Differential gene expression: origins through asymmetry and perpetuation through epigenetic mechanisms such as DNA methylation	p. 294
Long range control of gene expression and imprinting	p. 298
Mechanisms resulting in monoallelic expression from biallelic genes in human cells	p. 302
The nonequivalence of the maternal and paternal genomes	p. 302
The unique organization and expression of Ig and TCR genes	p. 306
Instability of the human genome: mutation and DNA repair	p. 315
An overview of mutation, polymorphism, and DNA repair	p. 316
Simple mutations	p. 316
Classes of genetic polymorphisms and sequence variation	p. 317
Mechanisms that affect the population frequency of alleles	p. 319
Classes of single base substitution in polypeptide-encoding DNA	p. 321
Sex differences in mutation rate and the question of male-driven evolution	p. 326
Genetic mechanisms which result in sequence exchanges between repeats	p. 329
Pathogenic mutations	p. 331
The pathogenic potential of repeated sequences	p. 337
DNA repair	p. 344
Our place in the tree of life	p. 351
Evolution of gene structure and duplicated genes	p. 352
Intron groups	p. 353
Symmetrical exons and intron phases	p. 355
Gene duplication mechanisms and paralogy	p. 357
Evolution of chromosomes and genomes	p. 361
The universal tree of life and horizontal gene transfer	p. 362
Molecular phylogenetics and comparative genomics	p. 372
What makes us human?	p. 377
A glossary of common metazoan phylogenetic groups and terms	p. 383
Evolution of human populations	p. 385
Coalescence analyses	p. 389
Mapping and identifying disease genes and mutations	p. 395
Genetic mapping of Mendelian characters	p. 397
Recombinants and nonrecombinants	p. 398
Genetic markers	p. 402
The development of human genetic markers	p. 403
Informative and uninformative meioses	p. 404
Two-point mapping	p. 404
Calculation of lod scores for the families in Figure 13.6	p. 406
Multipoint mapping is more efficient than two-point mapping	p. 407
Bayesian calculation of linkage threshold	p. 407
Fine-mapping using extended pedigrees and ancestral haplotypes	p. 408
Standard lod score analysis is not without problems	p. 411
Identifying human disease genes	p. 415
Principles and strategies in identifying disease genes	p. 416
Position-independent strategies for identifying disease genes	p. 416
Positional cloning	p. 418
Transcript mapping: laboratory methods that supplement database analysis for identifying expressed sequences within genomic clones	p. 421
Use of chromosomal abnormalities	p. 423
Mapping mouse genes	p. 423
Pointers to the presence of chromosome abnormalities	p. 426
Position effects - a pitfall in disease gene identification	p. 427
Confirming a candidate gene	p. 428
CGH for detecting submicroscopic chromosomal imbalances	p. 428
Eight examples illustrate various ways disease genes have been identified	p. 429
Mapping and identifying genes conferring susceptibility to complex diseases	p. 435
Deciding whether a non-Mendelian character is genetic: the role of family, twin and adoption studies	p. 436
Segregation analysis allows analysis of characters that are anywhere on the spectrum between purely Mendelian and purely polygenic	p. 437
Linkage analysis of complex characters	p. 439
Correcting the segregation ratio	p. 439
Association studies and linkage disequilibrium	p. 442
Measures of linkage disequilibrium	p. 443
The transmission disequilibrium test (TDT) to determine whether marker allele M[subscript 1] is associated with a disease	p. 446
Identifying the susceptibility alleles	p. 447
Sample sizes needed to find a disease susceptibility locus by a whole genome scan using either affected sib pairs (ASP) or the transmission disequilibrium test (TDT)	p. 447
Eight examples illustrate the varying success of genetic dissection of complex diseases	p. 448
Alzheimer disease, ApoE testing and discrimination	p. 452
Overview and summary	p. 457
Molecular pathology	p. 461
Introduction	p. 462
The convenient nomenclature of A and a alleles hides a vast diversity of DNA sequences	p. 462
A first classification of mutations is into loss of function vs. gain of function mutations	p. 462
The main classes of mutation	p. 462
Nomenclature for describing sequence changes	p. 463
A nomenclature for describing the effect of an allele	p. 463
Loss of function mutations	p. 465
Hemoglobinopathies	p. 465
Guidelines for assessing the significance of a DNA sequence change	p. 466
Gain of function mutations	p. 469
Molecular pathology: from gene to disease	p. 471
Molecular pathology of Prader-Willi and Angelman syndromes	p. 472
Molecular pathology: from disease to gene	p. 478
Molecular pathology of chromosomal disorders	p. 480
Cancer genetics	p. 487
Introduction	p. 488
The evolution of cancer	p. 488
Oncogenes	p. 489
Two ways of making a series of successive mutations more likely	p. 489
Tumor suppressor genes	p. 492
Stability of the genome	p. 497
Control of the cell cycle	p. 501
Integrating the data: pathways and capabilities	p. 502
What use is all this knowledge?	p. 504
Genetic testing in individuals and populations	p. 509
Introduction	p. 510
The choice of material to test: DNA, RNA or protein	p. 510
Scanning a gene for mutations	p. 511
Testing for a specified sequence change	p. 515
Multiplex amplifiable probe hybridization (MAPH)	p. 518
Gene tracking	p. 521
Two methods for high-throughput genotyping	p. 524
The logic of gene tracking	p. 527
Population screening	p. 529
Use of Bayes' theorem for combining probabilities	p. 529
DNA profiling can be used for identifying individuals and determining relationships	p. 532
The Prosecutor's Fallacy	p. 535
New horizons: into the 21st century	p. 537
Beyond the genome project: functional genomics, proteomics and bioinformatics	p. 539
An overview of functional genomics	p. 540
The function of glucokinase	p. 541
Functional annotation by sequence comparison	p. 541
Global mRNA profiling (transcriptomics)	p. 545
Sequence sampling techniques for the global analysis of gene expression	p. 547
Proteomics	p. 553
Protein chips	p. 554
Mass spectrometry in proteomics	p. 557
Determination of protein structures	p. 563
Structural classification of proteins	p. 567
Summary	p. 572
Genetic manipulation of cells and animals	p. 575
An overview of gene transfer technology	p. 576
Principles of gene transfer	p. 576
Methods of gene transfer to animal cells in culture	p. 578
Selectable markers for animal cells	p. 579
Isolation and manipulation of mammalian embryonic stem cells	p. 582
Using gene transfer to study gene expression and function	p. 594
Reporter genes for animal cells	p. 595
Sophisticated vectors used for insertional mutagenesis	p. 599
Creating disease models using gene transfer and gene targeting technology	p. 599
The potential of animals for modeling human disease	p. 603
New approaches to treating disease	p. 609
Treatment of genetic disease is not the same as genetic treatment of disease	p. 610
Treatment of genetic disease	p. 610
Using genetic knowledge to improve existing treatments and develop new versions of conventional treatments	p. 610
The ethics of human cloning	p. 614
Principles of gene therapy	p. 616
Methods for inserting and expressing a gene in a target cell or tissue	p. 616
Germ line versus somatic gene therapy	p. 617
1995 NIH Panel report on gene therapy (Orkin-Motulsky report)	p. 619
Designer babies	p. 619
Methods for repairing or inactivating a pathogenic gene in a cell or tissue	p. 624
Some examples of attempts at human gene therapy	p. 625
Glossary	p. 631
Disease index	p. 645
Index	p. 647
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